Role of organic cation transporters in the renal handling of therapeutic agents and xenobiotics

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Abstract

Organic cations (OCs) constitute a diverse array of compounds of physiological, pharmacological, and toxicological importance. Renal secretion of these compounds, which occurs principally along the proximal portion of the nephron, plays a critical role in regulating the concentration of OCs in the plasma and in clearing the body of potentially toxic xenobiotic OCs. Transepithelial OC transport in the kidney involves separate entry and exit steps at the basolateral and luminal aspects of renal tubular cells. It is increasingly apparent that basolateral and luminal OC transport reflects the concerted activity of a suite of separate transport processes arranged in parallel in each pole of proximal tubule cells. Most of the transporters that appear to dominate renal secretion of OCs belong to a single family of transport proteins: the OCT Family. The characterization of their activity, and their localization within distinct regions of the kidney, has permitted development of models describing the molecular and cellular basis of the renal secretion of OCs.

Section snippets

Molecular Physiology of OCTs

OCT1 was cloned from a rat renal cDNA library (Gründemann et al., 1994) and proved to be the initial member of a large family of transport proteins (the OCT Family, here referred to collectively as the ‘OCTs’). Within the Human Genome Organization (HUGO) Nomenclature Committee Database, the OCTs and their homologues have been organized into the SLC22A Family of solute carriers (Hediger et al., 2004). Additionally, the OCTs are recognized as being members of the Major Facilitator Superfamily of

Molecular determinants of OCT selectivity

It would be of obvious value to be able to predict with reasonable precision the extent to which individual elements of the renal OC secretory process interact with the vast array of physiologically and pharmacologically important Type I OCs. Moreover, a reasonably precise predictive model of substrate–transporter interaction could play a critically important role in the design of new pharmacological agents. The hallmark ‘multispecificity’ of renal OC secretion, as commented on earlier, has

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      OCTs transport many drugs such as beta-blockers, quinidine, cisplatin, morphine, metformin, phenoxybenzamine, prazosin, procainamide, and cimetidine (Ciarimboli et al., 2005; Kimura et al., 2005; Koepsell et al., 2007). Thus, the renal OCTs are important determinant of drug efficacy and toxicity (Ciarimboli et al., 2005; Wright 2005; Choi and Song, 2008). It has been reported that metformin fails to reduce fasting plasma glucose in type 2 diabetes patients who have mutation of OCT1 which is explained by decreasing hepatic uptake of metformin (Shu et al., 2007).

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